Dataset Information
Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing.
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ABSTRACT: Background
Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control.Objectives
This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control.Methods
The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integrated into a safe harbor AAVS1 locus using zinc finger nuclease technology.Results
Patch-clamp recording revealed that the edited iPSC-derived cardiomyocytes (iPSC-CMs) displayed characteristic long QT syndrome phenotype and significant prolongation of the action potential duration compared with the unedited control cells. Finally, addition of nifedipine (L-type calcium channel blocker) or pinacidil (KATP-channel opener) shortened the action potential duration of iPSC-CMs, confirming the validity of isogenic iPSC lines for drug testing in the future.Conclusions
Our study demonstrates that iPSC-CM-based disease models can be rapidly generated by overexpression of dominant negative gene mutants.
SUBMITTER: Wang Y
PROVIDER: S-EPMC4149735 | biostudies-literature | 2014 Aug
REPOSITORIES: biostudies-literature
Publications
Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing.
Journal of the American College of Cardiology 20140801 5
<h4>Background</h4>Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control.<h4>Objectives</h4>This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control.<h4>Methods</h4>The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integr ...[more]